Intro Puzzles
The Foldit "intro puzzles" are intended as an easy introduction to the tools and techniques used in the game. You'll find tips for each intro puzzles below. There's also a link to a video for each puzzle, provided by Foldit player Madde. Try to complete each puzzle without help first. The first few puzzles should be very easy, but none of the puzzles should take more than a couple of minutes. If you get stuck, you can reset the puzzle using "Reset Puzzle" from "Actions" in the lower left or the by the keyboard shortcut ctrl-r. If you have additional questions, ask online in the Foldit client using "Chat - Global", or "Chat - Group". See Foldit chat for more on Foldit chat. The following translations of this page are available: Deutsch | Svenska | Español | German | Russian | Japanese. Sidechains The Level 1 puzzles introduce sidechains and demonstrate ways to fix clashes. The puzzles also show how to move the protein around, and include an example of using one of the built-in tools to fix a problem. 'One Small Clash' In this puzzle, a small piece of protein has two sidechains. A spiky red ball shows that the sidechains are clashing. You can drag the sidechains with the mouse. Get rid of the clash by clicking and dragging one of the sidechains away from the other. Technical stuff: this puzzle has only three segments. The orange hydrophobic sidechain on the left is tyrosine. The blue hydrophilic sidechain on right is either glutamate or glutamine, which have the same shape. There's a segment in between the two sidechains, which is glycine. Glycine has no sidechain. Madde's "One Small Clash" video 'Swing It Around' This puzzle starts with the sidechains facing away from you. The first step is to click and drag on the white background to rotate the protein so you can see and grab the sidechains. Once you can see the sidechains, drag the sidechains on each end away from each other to clear the clashes and solve the puzzle. Technical stuff: this puzzle has five segments. The sidechains are all hydrophilic. The big sidechain on the left is lysine, and the big sidechain on the right is arginine. The sidechain in the middle is threonine. Threonine has the same shape as valine, but valine is hydrophobic, so it would be orange. In between the segments withsidechains, there are two segments of glycine. Madde's "Swing It Around" video 'Shake!' Like the first two puzzles, there are clashes between sidechains when this one starts. This puzzle introduces the shake tool. Shake automatically moves all the sidechains, trying to find a better position. To solve the puzzle, click on the shake button in the lower left of the window. The clashes should clear. Click on one of the stop button to finish the puzzle. Technical stuff: this puzzle shows two helices (or maybe "helixes"). The two helices are connected by a section of loop. The two previous puzzles had only sheets. More on helices, sheets, and loops later. Madde's "Shake!" video Backbone packing Level 2 introduces the backbone, the part which holds the protein together. The sidechains are attached to the backbone. This level also introduces voids, which happen when there are empty spaces in the protein. In some ways, voids are the opposite of clashes. Finally, in this level wiggle tool becomes available. Wiggle and shake are the most basic tools in Foldit. 'Backbones Collide' Like the earlier puzzles, the goal of this puzzle is to clear a clash. The shake tool is still available. Shaking helps the score, but it doesn't clear the clash. To fix this clash, grab the backbone of the protein at one of the ends, and drag it away from the backbone on the other end. Technical stuff: this protein looks at lot like the one in the previous puzzle, "Shake!". Dragging on the ends of one of the two helixes in this puzzle is the key. Madde's "Backbones Collide" video 'Close the Gap' This puzzle starts with several voids in the middle of the protein. Voids appear as translucent red spheres. The idea is to drag the ends of the protein toward each other. This puzzle can be a little tricky compared to the earlier ones. If you drag the ends too close together, you'll see the voids turn into clashes. Using the shake tool may help clear the clashes, but you may need to reset and try again a few times. You don't need to totally eliminate the voids, but they should be much smaller. Using shake at the end may help finish the puzzle. The two curly helixes should be parallel to each other when you're done. Technical stuff: voids happen when a protein is not "tightly packed" enough. They're bad because water could get into the empty space, which would tend to break the protein apart. Madde's "Close the Gap" video 'Wiggle!' This puzzle starts as a mess. There are large voids, and several hydrophobics have nasty-looking yellow blobs that mean they are exposed to the water surrounding the protein. The new wiggle tool fixes many of these problems. Just click on wiggle, let it run for a bit, then click on stop. This should solve the puzzle, no dragging required. You can also use the shake tool to score even more points. Try using wiggle, shake, then wiggle again. Technical stuff: wiggle is what the scientists may call a "minimizer". Behind the scenes, wiggle is doing calculations, trying to minimize the "free energy" in the protein. Free energy is bad because it tends to push the protein apart. As free energy goes down, your score goes up. Madde's "Wiggle!" video Hydrogen Bonding Level 3 introduces hydrogen bonds, another thing that holds proteins together. Hydrogen bonds show as blue-and-white "candy canes" in Foldit. This level includes techniques for lining up sheets that are used all the time by Foldit players. It also introduces the rebuild, which searches for new shapes for your protein. 'Sheets Together' This puzzle has two sheets. If you look closely, there's already a hydrogen bond -- a blue-and-white "candy cane" -- between the sheets. If you drag the sheets closer together, you'll see more hydrogen bonds form between the sheets. If you drag the sheets too close, you'll get clashes. Shake and wiggle to finish the puzzle. Technical stuff: a sheet by itself doesn't do too much good. A single sheet is sometimes called a "strand", which may tell you something. When sheets are bonded together edge-to-edge like this, they help to stabilize the protein. Madde's "Sheets Together" video 'Lonely Sheets' Time to match up some sheets! Wiggle doesn't always work by itself. You can connect these sheets with [[Rubber Bands|'RUBBER BANDS']] . Hold shift (or click on middle button) and drag from one to the other. Try it with this sheet! Hold shift and drag. Rubber Bands pull together when you Wiggle. Don't worry about individual sidechains. Try connecting the sheets with a Rubber Band. Tip: Put rubber bands between two little sheets, wiggle, remove bands, shake and wiggle Madde's "Lonely Sheets" video 'Sheets and Ladders' These sheets have been torn apart! Rubber Bands are free! Make as many as you want. You can move the view around and drag the background. When you're close, you can remove the bands and Wiggle again. Tip: Put a rubber band at each end of the sheet with the end of the sheet above, wiggle, remove the bands, shake and wiggle. The step ladder are the sheets and the side the bands. Madde's "Sheets and Ladders" video 'Lock and Lower' Foldit 1297974789.png Foldit 1297974837.png One of the sheets is out of place! Sheets like to be alongside each other. Remember, hydrogen bonds are great for your score. You can Freeze the sheets already in place. Hold shift and double click. Tip: one sheet is over the row, freeze the two sheets on each side of it, double click on them, put the sheet between this two, rotate to see if the protein is flat, shake and wiggle. Madde's "Lock and Lower" video 'Rebuild' You might have guessed by now, but ' color' is used to show how well part of the protein is folded. This loop appears to be a problem. You can deal with problem segments by using the You can deal with problematic segments by using the REBUILD tool. Rebuild tests out different shapes for the protein. Right click (for windows) on the backbone to start a Rebuild. You can stop when Rebuild finds the shape you want. Shake and Wiggle will take care of clashes. This looks like a good shape! Try a Shake and Wiggle to clean it up. You can Wiggle a single section. Right click and choose Wiggle. Tip: follow the instructions carefully, rebuild the red section and as usual shake and wiggle. After Rebuild you will almost always have a lower score, shake and wiggle before watching the score. Madde's "Rebuild" video Hydrophobics and Hydrophilics Level 4 introduces hydrophobics and hydrophilics. Orange sidechains are hydrophobic, and should be hidden on the inside of the protein. Blue sidechains are hydrophilic, and are OK on the outside of the protein. 'Hide the Hydrophobic' Orange sidechains are HYDROPHOBIC . They want to be buried inside the protein. These bubbles are called EXPOSEDS. ' EXPOSEDS' may appear on unburied hydrophobics! (yellow ball moving). Blue 'sidechains need plenty of space. They should point outward. Orange sidechains should be kept surrounded. Hide it in the empty space in the protein's interior and move the blue hydrophilic away outside. Your score measures not only clashes, but also how well hydrophobics are hidden. ''Tip: Move the orange sidechain in the center. Madde's "Hide the Hydrophobic" video '''Turn It Down Sometimes you need to rotate to bury the hydrophobics. You can rotate with the TWEAK tool. Right click the helix to find it. Click and hold the purple arrows to rotate. Click stop to finish the Tweak. The helix has turned and exposed a hydrophobic! Madde's "Turn It Down" 'Flippin' Sheets' One of these sheets has unburied hydrophobics. You can easily flip a sheet with Tweak. The straight (purple) arrows turn the sheet 180 degrees and shift it to maintain hydrogen bonds. Look for the sheet with the exposed hydrophobics, and click the new straight arrows on the Tweak tool to shift and flip it. You're almost there! Try a Wiggle to finish up. Flip the sheet with oranges out in the right direction, then shake until the score is > 5000 then wiggle LennStar's guide: This is one puzzle that really dislikes being mishandled. It took me at least 5 tries. This is how to do it: If you already have done anything to it, reset the puzzle. (Hint: You propably have to move the 4 sheets to the foreground, the one with the arrow pointing on with the short end to the left. You can also go back to puzzle menu to get the right view.) Now right click on the one sheet where the arrow from the text points to. Click tweak. Now click one time on the straight arrow to the right. Now the sheet should flip. use shake and wiggle it. That should raise your score to the needed points. Madde's "Flippin' Sheets" video 'The Right Rotation' Orange pointing in, blue pointing out. Right click a helix to Tweak it. Tip: turn the helix shown to hide the orange, expose the blue, shake and wiggle Madde's "The Right Rotation" video 'Structure and Rebuild' Changing the structure of the protein can help you Rebuild. All these segments should be helices. Double click this loop to select the entire secondary structure. To enter Structure Mode, click the Modes tab and choose Structure, or press 2. Press 2 to enter Structure Mode. Click here to assign the selected part to helices Then start to Rebuild. You can stop when it Rebuilds to something look like a complete helix (Like a spring). Try a Shake and Wiggle to clean it up. (Don't forget to unselect the puzzle by clicking any place on the background in order to do global Wiggle.) You can click on this part that is already helix and hold your mouse down. Drag your mouse to the end. Did you see the change? Now switch back to Pull Mode, and try to rebuild the whole thing to see what's going to happen. Right click on any segments and start Rebuilding. You can stop when it Rebuilds to something look like a whole long helix (Like a spring). And try a Shake and Wiggle to clean it up. Tip: Reset and follow the instructions with care. Rebuild a long time. Madde's "Structure and Rebuild" video Tools and Types Level 5 introduces some of the different puzzle types found in Foldit.< 'Quest to the Native' In this puzzle, the correct solution, called a NATIVE, is known. To align the guide with a specific section of the protein, Right click any segment and click ALIGN GUIDE. Use the tools available to match the protein with the guide. If you haven't discovered it yet, you can attach a rubber band from the protein to a point in empty space. Rubber bands also affect the pull tool, not just wiggle. Remember to freeze parts of the protein that you don't want warped by wiggle or pull. Tip: Put bands and wiggle to move most of the protein inside the cloud. Remove the band, shake and wiggle. Madde's "Quest to the Native" video 'Movin' Along' Sometimes you can MOVE whole pieces of the protein. Click on a piece to bring up the MOVE tool. Then press and hold down RIGHT BUTTON (CTRL on Mac) anywhere on the tool to drag the piece around. You can't pull on the backbone of this puzzle. Tip: Click on the helix, then in the middle of the purple cross with the right button of your mouse (use crtl+click on Mac), then drag the helix on the shadow (if the helix rotates, you have click two times the left button), shake, rotate the view to check the sidechains then wiggle. Reset and redo, many players don't have success the first time. Madde's "Movin' Along" video 'Electron density' In an Electron Density puzzle, we only have data on the rough shape of the protein. You are given this data as a 3D surface that predicts the general areas where parts of the protein are located. The backbone of the protein will fit neatly inside the 3D region, but it's up to you to work out how it fits. Click on the ELECTRON DENSITY button. These options let you control how the density surface is drawn. Adjust the THRESHOLD to change the thickness of the density region. At a good threshold, you can see shapes in the region that match parts of the protein. After moving the protein press ALIGN PROTEIN TO DENSITY to line up the surface with the protein. The alignment usually takes a few seconds to complete. Use Shake, Wiggle, and careful moving to fold the protein into the best possible shape that fits inside the predicted region. Tip: Wiggle, shake, wiggle, shake, then drag the end of protein inside the cloud with caution, shake, wiggle. You can also put bands to join the sheets together inside the cloud. Madde's "Electron Density" video 'Exploration' In exploration puzzles like this one, your goal is to find a solution that is different from the starting structure. Your calculated score will be the protein's base score times an exploration multiplier for finding new configurations. You can use the Contact Map to help you find new configurations for the protein. The rows and columns in Contact Map correspond to segments of the backbone. A black mark indicates that the segments corresponding to that row and column are in contact. The red areas are contacts present in the starting structure. White areas are new contacts, which increase your score multiplier. You can click on TUTORIAL to learn more about Exploration puzzles. Use all the tools you have learned to fold this protein into a new shape. Don't be afraid to break some connections to make new ones. Tip: Try lining up all 4 sheets with bands. Madde's "Exploration" video 'Control Over Clashing' You may have noticed that using Wiggle when there are many clashes causes the protein to come apart. To avoid this, lower the CLASHING IMPORTANCE . This lets Wiggle keep making small adjustments even if the protein is packed too tight. A lower Clashing Importance also lets you make moves that add clashes without unraveling the protein, like pulling on a tangled strand. Try setting Clashing Importance to 0.1, then Wiggle while slowly increasing it. Tip: Follow the instructions, move the clashing importance by step and wiggle until the score decrease. If the protein explose, reset and redo more slowly. Madde's "Control Over Clashing" video Sequences Level 6 introduces the alignment tool. 'Basic Threading' These levels will introduce the powerful [[The Alignment Tool|'ALIGNMENT']] tool! It will let you use the structures of real proteins, called TEMPLATES, by THREADING. Click on the smiley button to bring up the ALIGNMENT tool. This 3D structures shows the backbone of the template. The bottom row of the letters is the TEMPLATE SEQUENCE. you can see it in 3D as spheres connected by lines. The top row of letters is the sequence of your protein. The cylinders in 3D show how its backbones lines up with the template. When you THREAD, your protein will try to fit onto the 3D template where the cylinders are. Click the little smiley to try threading. Now that you've threaded it, try a shake and wiggle! In this puzzle, you'll just need to use the ALIGNMENT tool to thread, then wiggle and shake. Don't worry about making manual adjustments. In this puzzle, you'll just need to use the ALIGNMENT tool to thread, then shake and wiggle. Madde's "Basic Threading" video 'Cut and paste' This blue band is a CUT. A CUT appears when the backbone of the protein has been cut. You need to close the CUT to complete the puzzle! To close the CUT, left click on one segment to bring up the MOVE tool, and then move the pieces together until the CUT turns yellow. Then click the CUT. Now SHAKE and WIGGLE to finish up! Tip: the move tool : left click then right click on the purple cross. Madde's "Cut and paste" video 'Alignin' Sequences' Bring up the alignment tool again. This time the letters and colors in the sequences are not lined up well.This middle row shows how well each letter matches; a bigger white bar means a better match. And this score (on the right) shows how the sequences match overall . You can click and drag or use the arrow keys to move the letters around. Try to line up the colors. It's okay if there are spaces, but fewer spaces is better. Enabling THREADING will let you see the changes to the protein now, or you can wait until you're done to THREAD. When there's a gap in the aligment, a CUT is inserted. When you're done aligning, move the two pieces together, then WIGGLE and click when the band turns yellow to close the cut. Good, now SHAKE and WIGGLE to finish up!" Tip: follow the instructions carefully. '' Madde's "Alignin' Sequences" video Protein Design Level 7 introduces Foldit design puzzles, which give players the chance to design new proteins. Some of these designs actually get turned into real proteins in the Foldit lab, see design puzzle results for more. 'Intro to Design' Welcome to the design puzzles. In these challenges you will have the power to design new proteins! Segments with brighter colors can be designed! Some of these sidechains are too large. You can change them in Design Mode. To enter Design Mode, click the Modes tab and choose Design, or press 4. Select the segments you want to mutate. Click the Mutate Button from the menu. Then click the picture of the sidechain you want to mutate to Try to find better fits for both designable sidechains. If you're stuck, it may be easier to restart from the beginning. Madde's "Intro to Design" video '''Swappin' Side Chains' Now some sidechains are too small, causing voids! Try replacing them with some large ringed hydrophobics. You'll need to change to Design Mode. Madde's "Swappin' Side Chains" video 'Mass Mutate' This helix has a lot of unburied orange hydrophobics. You can change them to blue hydrophilics in Design Mode. You've earned a new tool! Mutate Sidechains is like Shake, but may mutate designable sidechains. Stop the Mutate Sidechains by pressing the space bar. Tip: Don't reset on this puzzle, go to menu/ intro puzzle and click on mass mutate. Madde's "Mass Mutate" video 'Insertion and Deletion' This red line is a CONSTRAINT, indicating that the segments it connects should be closer together. You can change the length of the helix by inserting or deleting segments. Right click a segment of the helix and use Insert Between. The blue blinking segments will show you where it will appear. The protein seems a little short now. You may want to undo or insert a segment. You can use wiggle and mutate sidechains to finish up. The protein seems a little long now. You may want to undo or delete a segment. Madde's "Insertion and Deletion" video More Molecules Level 8 introduces ligands. 'Ligand Debut' These levels contain molecules other than proteins! This small molecule is a LIGAND. Proteins can be designed to bind ligands. Hydrogen bonds are important for binding ligands. Connect red atoms with blue atoms to form bonds between the ligand and sidechains! Left click on the ligand to bring up MOVE tool. RIGHT-button-drag to move left, right, up, and down, LEFT-button-drag to rotate and SHIFT-LEFT (or MIDDLE) -button-drag to move ligand Into/Out of screen. When the ligand is in a good place, try a wiggle! Madde's "Ligand Debut" video 'Ligand Constraints' These are CONSTRAINTS. Red constraints are violated. Make the constraints become green! After moving the ligand closer, use WIGGLE SIDECHAINS to wiggle the sidechains and the ligand at the same time. Try and compare it to Shake Sidechains. Madde's "Ligand Constraints" video 'DNA Pairing' Use Design Mode to find the correct match for the incorrectly paired sidechains. DNA sidechains pair according to color and size. Match sidechains of same color and opposite sizes to make lots of bonds! Match sidechains of the same color and opposite sizes to form lots of hydrogen bonds! Look at this big yellow sidechain with a small yellow sidechain. Use Design Mode to find the right match for the incorrectly paired purple sidechains! Madde's "DNA Pairing" video 'DNA and Protein' DNA can hydrogen bond to protein. Mutate the proteins to form better bonds. Try adding a long hydrophilic here. Try a shorter, forked hydrophilic here. Madde's "DNA and Protein" video Category:Help Category:Help foldit